1-alkyl-(n-benzyl-n-alphapyridylamino)-piperidines and their production



Patented Feb. 7, 1950 l-ALKYL- (N-BENZYL AMINO -PIPER1DIN DUCTION-N-ALPHAPYRIDYL- ES AND THEIR PEO- Robert H. Reitsema, Kalamazoo, Mich.,assignor to The Upjohn Company, Kalamazoo, Mich., a corporation ofMichigan No Drawing. Application June 18, 1949, Serial No. 100,087

5 Claims. (01. 260-293) wherein R is a lower-alkyl radical containingfrom one to eight carbon atoms, inclusive, one B is hydrogen and theother R is the N-benzyl- N-alpha-pyridylaminoradical having the formula-The new tertiary amines are high-boiling substances which are viscousliquids or solids at room temperature, readily soluble in most commonorganic liquids, and only slightly soluble in water. The free bases formaddition salts with mineral with a 2-halopyridine, preferably withZ-bromoacids such as hydrochloric, hydrobromic, and 5111- furic; withorganic carboxylic acids such as acetic, lactic, tartaric, and succinic;and with picric acid. The acid salts are usually very water soluble.Some salts, e. g., the hydrochlorides, have such a strong affinity forwater that it is difficult to obtain them in an anhydrous form. Thesalts can, however, be prepared readily in aqueous solution.

The compounds of the invention, have three strongly basic tertiary aminogroups and are capable of forming salts with from one to threeequivalents of an acid. The monoand di-acid salts may be formed bymixing the stoichiometric quantity of the acid with a solution of theamine and evaporating to dryness. An excess of acid gives only thetri-acid salt of the base. When the salt is used for therapeuticpurposes, since the therapeutic activity residesin the basic portion ofthe molecule, the acid groups attached thereto are of significance onlyin that they should be non-toxic and in that they dilute the efiec-'tiveness of the molecule, on a weight basis, in

proportion to their number.

The new l-alkyl-(N-benzyl-N-alphapyridylamino) -piperidines can beprepared by the alkyl-.

ation of a l-alkyl-3-benzylaminopiperidine or a l-alkyl-4benzylaminopiperidine, respectively,

pyridine or 2-chloropyridine.

The 1-alkyl-benzylaminopiperidines useful as the method of the present.

starting materials in invention, together with a method for theirpreparation, are described and claimed in prior filed copendingapplications Serial No. 24,426, now, abandoned, filed April 30, 1948,and Serial No. 29,413, now abandoned, filed May 26, 1948, and inconcurrently filed copending application Serial No. 100,088, now Patent2,496,958. According to the methodclaimed in the applications referredto, a l-alkyl-piperidone is condensed with benzylamine to form al-alkyl-benzyliminopiperidine and the latter then hydrogenated to form a1- alkyl-benzylaminopiperidine, the condensation and hydrogenationgenerally being carriedout in a single step.

The alkylation requires an elevated temperature and the presence in thereaction mixture of an acid-binding agent. In some instances analkylation catalyst maybe helpful. The alkyla tion can be conductedWithout a diluent or with a diluent such as toluene, xylene, or cymene,as desired. Various catalysts useful in alkylating amines, such asfinely divided copper-bronze, can be used if desired. Anhydrous metalcarbonates or bicarbonates are useful acid-binding agents, those of thealkali metals being preferred. An excess of the starting amine can alsobe used for acid-binding purposes. carried out by mixing the reactantsand catalyst together in substantially equimolar proportions with orwithout a diluent and heating, e. g. to a temperature of about 160-180degrees centigrade. The length of the period of heating is not ofcritical importance, periods of from 5 to hours being suitable.

The reaction product can be treated for separation and purification ofthe formed product in any one of several ways known to the art. Forexample, after cooling, water is added and the copper-bronze or othercatalyst, if employed, removed by filtration. lyst aids in separation ofthe water layer from the organic layer, the latter containing most ofthe product. After separation, the water layer is extracted with awater-immiscible solvent such as ether, benzene, or xylene. This Thealkylation can be The early removal of cata-' extract, after separationfrom water, is combined with the organic layer, the combined solutionsare dried, the solvent is removed, and the resulting l-alkyl-(N-benzyl-N-alphapyridylamino)-piperidine is isolated and purifiedbydistillation, crystallization,

or both. Other ways of isolating and purifying the products will beapparent to those familiar with the art.

Emample 4.-1 ethyl-4-(N-benzyl-N-alphapyri- Salts of the amines withacids can be prepared in various ways known to theart. If an "1 aqueoussolution of the salt is desired, the free amine can be titrated withacid in an aqueous medium until the resulting solution has attained thedesired pH. If it is desiredto isolate the 1 amine salt, this can bedone by evaporating its solution to dryness. Alternatively, a solutionof acid, the solvent chosen being one in which the amine salt isinsoluble, whereupon the insoluble salt precipitates. Manyof the saltsare hygroscopic 'in nature. some are freed from solvent only withdifliculty.

The following examples illustrate the inventionbut are not to beconstrued as limiting.

Example 1 .-1 -ethyl-4-benzylaminopiperidine Thirty-four and five-tenthsgrams of l-ethyl- 4-piperidone (Fuson, Parham and Reed, J. Am.Chem.'Soc. 68, 1239 (1946)) and 27. 9 gramsof benzyl-amine werethoroughly mixed-at a temperature-between -25'degrees centigrade. To thereaction mixture was then added 50 milliliters of absolute alcohol andabout 0.2 gram of Adam's platinum oxide catalyst. The alcoholic solutionwas shaken under'a hydrogen pressure of about 50 pounds Der-square inchat room temperature in a suitable apparatus. The absorption of hydrogenwas-complete after about two hourspwhereupon the catalystwas removed byfiltration and the resulting l-ethyll-benzylaminopiperidine, boiling at113-115 =degrees centigrade-at a pressure 'of- 0.2 millimeter, wasisolated by distillation. The dipicrate thereof melts at 227-228 degreescentigrade and the dihydrochloride' melts at 303-3045 degreescentigrade' with decomposition.

Example 2.1 -rmethyl-4-benzylaminopiperidine In a'manner similar toExample 1, there was obtained from l-methyli-piperidone and benzylamine, l-m'ethyl-4-benzylaminopiperidine, boiling at 168 to 172 degreesCentigrade at 17 millimeters of mercury pressure. Its dipricate melts at225.5 to 227degrees centigrade with decomposition.

Example 3.-1 methyl 4 (N-benzyl-N-alpha: pyridylamino) -z iperidine To astirred'suspension of 23.5 grams of 1'- methyl-4-benzylaminopiperidine,15.0 grams of anhydrous potassium carbonate and 0.2 gram offinelydivided copper-bronze powder, there was added 18.2 grams of2-bromopyridine. The temperature of the reaction mixture was then raisedto about 160-180 degrees centigrade Where it was maintained for about 45hours. The mixture was cooled to about room temperature and mil1i-'liters of Water added. After the copper-bronze powder was removed byfiltration, the aqueous layer was separated from the organic layer andextracted with ether. The ether extract was combined withthe organiclayer previously sepa-- rated, the combined layers dried, ether removed,and the residual l-methyl-i- (N -benzyl-N-alphapyridy1am'ino)-piperidinedistilled at 188-189 dedylamino) -piperidine In a manner similar toExample 3 from l-ethyl- 4 benzylaminopiperidine and 2 bromopyridinethere was'obtained 1-ethyl-4-(N-benzyl-N-alphapyridylamino),-piperidine,boiling at 188-194 vdegrees'centigradelunder a pressure of 0.6millimeter of mercury. The dipicrate thereof melted ;at 217-218 degreescentigrade after crystallizathe amine can be reacted with a solution ofan fu Q from ethanol- E'xample 5 To 177.9 grams of ethylN-ethylaminoacetate was added with cooling 132.0 grams of ethyl-ybromobutyrate. The reaction mixture was allowed to stand for threedays at room temperature. The ethyl "N-ethylaminoacetate hydrobromidewhich precipitated was removed by filtration. The residual liquid wasdistilled under. a pressure of 20 millimeters of mercury, whereupon109grams of ethyl y-(N-carbethoxymethyl- N-ethylamino) -butyrate,distilling at 161-163 degrees centigradeyrt 1.4392, was obtained.

Example 6 The ester from Example 5 was cyclized by the technique of J.Am. Chem.'S0c. 68 (1946), whereupon l-ethyl-B-piperidone hydrochloride,melting at 172-1735 degrees centigrade was obtained.

Example 7 Forty and nine-tenths: grams of 1-ethyl-3- piperidonehydrochloride and 23.4 mols of benzyl aminewere thoroughly mixed-at atemperature between 15and-25 degreescentigrade. To the reaction mixturewas .then' added milliliters of methanol and 1 about: 0.2:; gram. of.platinum oxide catalyst. The alcoholic solution was shaken under ahydrogen pressure of about 50 pounds Example 8 In: a'manner similartoExample 7 there was obtained from l methyl -br-piperidone (J. Am.-ChemsSoc. 55,1233 (1933)) and benzyl amine, 1 methyl 3benzylaminopiperidme boiling at 112-117. degrees centigrade at a;pressure of 1 millimeter of mercury; 11, 1.5299. Its dipicrate melts at191-193 degrees centigrade.

Other-compounds which may be produced according to the'proceduregiveninthe foregoing, and 'whichnare-included as starting materials withinthescope of the invention, ar the 1-alkyl-3-benzylaminopiperidines, whereinthe l-alkyl groupis propyl, isopropyl,=butyl, or thelike. These areprepared by employement in the process of the correspondingl-alkyl-3-piperidone. Ewample 9.'1-ethyl-3-'(N 4benzyl-N-alphapyridylamino) -piperidine 'To-a stirred-suspension of20.2'grams of 1- ethyl-3-benzylaminopiperidine, 12.8. grams or potassiumcarbonate and 0.2 gram of'copperbronze powder, there was added 14.6grams of 2-bromopyridine. The temperature of the reaction mixture wasthen raised to 160-170 degrees centigrade where it was maintained forabout 48 hours. The mixture was then cooled to about room temperatureand milliliters of water and milliliters of ether added. After thecopper-bronze powder was removed by filtration, the ether layer wasseparated and the aqueous layer again extracted with ether. The etherextracts were combined, the combined extracts dried, and the etherremoved and the residual l-ethyl-B-(N benzyl N aiphapyridylamino)-piperidine distilled at -170 degrees centrigrade under a pressure of 0.3millimeter of mercury. The product, on redistillation, boiled at -160degrees centigrade at 0.2 millimeter of mercury. The dipicrate melts at162-463 degrees centigrade with decomposition.

Example 1 0.-1 -methyl-3- (N -benzyl-N -alphapyridylamino) -pi1 eridineIn a manner similar to Example 9 from l-methly-3-benzylaminopiperidineand 2-bromopyridine there was obtained l-methyl-B-(N-benzyl-N-alboilingat 163-164 tyl-4-(N-benzyl-N-alphapyridylamino) piperldine, 1-propyl-,1-isopropyl-, 1-butyl-3-(N-benzyl-N-alphapyridyl-amino) piperidine, andthe like.

I claim:

1. A compound selected from the group con sisting of: (a)l-lower-alkyl-e-(N-benzyl-N- phapyridylamino)-piperidines andl-lower-allql-3- (N-benzyl-N-alpha-pyridylamino) piperidines wherein thelower-alkyl radical contains from one to eight carbon atoms, inclusive,and (b) salts thereof with acids.

2. 1-methyl-4-(N-benzyl-N alphapyridylamino) -piperidine.

3. 1-ethyl-4-(N-benZyl -N alphapyridylamino) -piperidine.

4. 1-ethyl-3-(N-benzyl N no) -piperidine.

5. The method which includes the step of heating a. compound from thegroup consisting of the l-alkyl-4-benzylaminopiperidines and the 1-alkyl-3-benzylaminopiperidines with a halopyridine from. the groupconsisting of 2-bromopyridine and 2-chloropyridine in the presence of anacid-binding agent to form a compound from the group consisting of thl-alkyll-(N-benzylalphapyridylamino) -piperidines and the l-alkyl- 3-(N-benzylalphapyridylamino) -piperidines.

ROBERT H. REITSEMA.

- alphapyridylami- No references cited.

1. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF: (A)1-LOWER-ALKYL-4-(N-BENZYL-N-ALPHAPYRIDYLAMINO)-PIPERIDINES AND1-LOWER-ALKYL-3-(N-BENZYL-N-ALPHA-PYRIDYLAMINO)-PIPERIDINES WHEREIN THELOWER-ALKYL RADICAL CONTAINS FROM ONE TO EIGHT CARBON ATOMS, INCLUSIVE,AND (B) SALTS THEREOF WITH ACIDS.
 5. THE METHOD WHICH INCLUDES THE STEPOF HEATING A COMPOUND FROM THE GROUP CONSISTING OF THE1-ALKYL-4-BENZYLAMINOPIPERIDINES AND THE 1ALKYL-3-BENZYLAMINOPIPERIDINESWITH A HALOPYRIDINE FROM THE GROUP CONSISTING OF 2-BROMOPYRIDINE AND2-CHLOROPYRIDINE IN THE PRESENCE OF AN ACID-BINDING AGENT TO FORM ACOMPOUND FROM THE GROUP CONSISTING OF THE1-ALKYL-4-(N-BENZYLALPHAPYRIDYLAMINO)-PIPERIDINES AND THE1-ALKYL3-(N-BENZYLALPHAPYRIDYLAMINO)-PIPERIDINES.